A liposome is a vesicle composed of one or more lipid bilayers, capable of carrying hydrophilic molecules within an aqueous core or hydrophobic molecules within its lipid bilayer(s). As used herein, “Lipid nanoparticles” (LNs) is a general term to described lipid-based particles in the submicron range. LNs can have structural characteristics of liposomes and/or have alternative non-bilayer types of structures. Drug delivery by LNs via systemic route requires overcoming several physiological barriers. The reticuloendothelial system (RES) is responsible for clearance of LNs from the circulation. Once escaping the vasculature and reaching the target cell, LNs are typically taken up by endocytosis and must release the drug into the cytoplasm prior to degradation within acidic endosome conditions.
In particular, the delivery of such nucleic acids (NAs), including siRNA and other therapeutic oligonucleotides is a major technical challenge that has limited their potential for clinical translation.
The development of efficient delivery vehicles is a key to clinical translation of oligonucleotide (ON) therapeutics. It is desired that a LN formulation should be able to (1) protect the drug from enzymatic degradation; (2) transverse the capillary endothelium; (3) specifically reach the target cell type without causing excessive immunoactivation or off-target cytotoxicity; (4) promote endocytosis and endosomal release; and (5) form a stable formulation with colloidal stability and long shelf-life.